title: Heparanase procoagulant activity is elevated in women using oral contraceptives.
abstract: OBJECTIVE
  What is the effect of estrogen on heparanase procogulant activity?
  
  
  CONCLUSIONS
  Estrogen increases heparanase procoagulant activity.
  
  
  BACKGROUND
  Estrogen therapy increases the risk of thrombosis and was previously found to up-regulate heparanase expression. Heparanase is involved in angiogenesis and metastasis, and has been shown to form a complex with tissue factor (TF) and also shown to enhance the generation of factor Xa.
  
  
  METHODS
  A case-control study. Thirty-four healthy women using oral contraceptives (OC) and 41 women not using hormonal therapy and not pregnant per history were enrolled, over a 5-month period, at the Rambam Medical Center, Haifa, Israel. In vitro, estrogen receptor-positive (MCF-7) and -negative (MDA-231) cell lines were incubated with estrogen, tamoxifen and ICI-182.780 a pure estrogen receptor antagonist. The cell medium was evaluated for TF/heparanase complex activity, TF activity and heparanase procoagulant activity by chromogenic substrate.
  
  
  METHODS
  Exclusion criteria included age <18 years, post-menopausal women, concomitant medications other than supplement minerals and vitamins, acute or chronic illness.
  
  
  RESULTS
  The study demonstrates increased risk of high heparanase procoagulant activity in OC users. When a cutoff level of 0.25 (absorbance 405-490 nm) was set, the odds ratio was 131 (P < 0.0001). When all results were studied by quartiles, in quartiles 3 and 4 the results were almost exclusively of the OC users (P < 0.0001). In cell cultures, estrogen and tamoxifen increased heparanase procoagulant activity in the medium of estrogen receptor-positive (MCF-7) cells.
  
  
  CONCLUSIONS
  The main limitation of the current study is that the two estrogens given to the women and cell cultures, ethinyl estradiol (EE) and 17-β-estradiol (E2), respectively, may have different effects on the coagulation system, although an increase in heparanase procoagulant activity was demonstrated in both of them. Although the sample size of the study group was limited, significant differences in the activation of the extrinsic coagulation pathway were demonstrated.
  
  
  CONCLUSIONS
  The clinical relevance of the heparanase procoagulant activity assay as a screening tool in thrombophilia work-up should further be elucidated.
authors.affiliation: Faculty of Medicine, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Matan
authors.forename: Elena
authors.initials: E
authors.lastname: Axelman
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brenner
authors.forename: Yona
authors.initials: Y
authors.lastname: Nadir
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D016022:Case-Control Studies; D002460:Cell Line; D003276:Contraceptives, Oral / Q000009:adverse effects*; D004958:Estradiol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D005966:Glucuronidase / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007557:Israel / Q000453:epidemiology; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012306:Risk; D020845:Selective Estrogen Receptor Modulators / Q000009:adverse effects / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000009:adverse effects / Q000494:pharmacology; D019851:Thrombophilia / Q000097:blood / Q000139:chemically induced* / Q000453:epidemiology / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D055815:Young Adult; D000099175:Heparanase
chemical_list: D003276:Contraceptives, Oral; D004958:Estradiol; D004965:Estrogen Antagonists; D004967:Estrogens; D000077267:Fulvestrant; D005966:Glucuronidase; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D013925:Thromboplastin; D000099175:Heparanase
keywords: coagulation; estrogen; heparanase; oral contraceptives; tamoxifen